Arginine Vasopressin (AVP), also known as antidiuretic hormone (ADH), is produced in the hypothalamus and released from the neuropituitary gland in conditions of high plasma osmolality, low plasma volume and low blood pressure. AVP binds to three different receptors (V1aR, V1bR and V2R). The V1aR is widely expressed (Nature 1993:356:523-526), whereas V1bR and V2R are more specifically expressed in the pituitary gland and kidney collecting ducts, respectively (Nature 1992:336-339 and FEBS Lett 1994:356:215-220). The antidiuretic effect of AVP is mediated through V2R and pharmacological blockade of V2R has favourable effects in the treatment of hyponatremia and heart failure whereas the prothrombotic and vasoconstrictor effects of AVP, which are used clinically in bleeding and hypotensive disorders are primarily mediated through the V1aR. In addition, AVP action has suggested to be linked to modulation of adrenocorticotropic hormone (ACTH) release (V1bR), stimulation of liver glycogenolysis (V1aR) and stimulation of insulin and glucagon secretion (V1aR) (Morel et al., Nature 1992; 356(6369):523-6; de Keyzer et al., FEBS letters 1994; 356(2-3):215-20; Ventura et al., Journal of molecular endocrinology 1999; 22(3):251-60).
Previous studies on humans and animal models have indicated a role of the AVP system in glucose homeostasis, insulin resistance and diabetes mellitus. In patients with poorly controlled diabetes mellitus and increased osmolality, plasma AVP is markedly elevated (Lolait et al., Nature 1992; 357(6376):336-9) and in healthy subjects AVP infusion leads to increased blood glucose levels (Schrier et al., N Engl J Med 2006; 355(20):2099-112). Mice lacking the V1aR display impaired glucose tolerance, insulin resistance and elevated AVP levels (Gheorghiade et al., Jama 2007; 297(12):1332-43; Federici et al., Annals of medicine 2007; 39(5):346-58) while mice who lack the V1bR has the opposite phenotype of lower fasting plasma glucose and increased in insulin sensitivity, in comparison with normal mice (Dunser et al., Circulation 2003; 107(18):2313-9).
The vasopressin gene encodes a precursor protein (pre-pro-AVP) comprising a 19 amino acid signal sequence, arginine vasopressin and two associated proteins, neurophysin II and a glycopeptide, copeptin. Copeptin is a biologically inactive cleavage product of the C-terminus of the AVP precursor and is produced in equimolar amounts with AVP. However, in contrast to AVP, copeptin is stable, has a long half-life, is not bound to platelets and therefore found in considerably higher concentrations in plasma than AVP, and it has been proposed as an alternative diagnostic target to assess vasopressin release (Struck J, Morgenthaler N G, Bergmann A. Copeptin, a stable peptide derived from the vasopressin precursor, is elevated in serum of sepsis patients. Peptides. 2005 December; 26(12):2500-4.).
AVP has been described as diagnostic marker for diabetes mellitus and it was known that AVP level is related with diabetes mellitus as an acute or chronic stressor using type I diabetes mellitus animal models. (Sun Shin Yi et al., Enhanced expressions of arginine vasopressin (Avp) in the hypothalamic paraventricular and supraoptic nucleic of type 2 diabetic rats, Neurochem Res (2008) 33:833-841)